Mercury is a significant contaminant of the environment and poses a serious systemic toxicity risk to humans, animals, and the aquatic food web. Published data indicate that inorganic mercury accumulates and induces strong renal toxicity and adversely affects spermatogenesis and fertility in male rats. Such effects underscore the threat to human health because mercury is ubiquitously present in the environment and is widely used in the industry. Hence, the long-term goal of this project is to understand how environmental exposure to mercury induces toxicity. The specific aim of this application is to determine the effects of mercuric chloride on differential gene expression in the kidney and two male reproductive organs. We hypothesize that the toxicity of mercuric chloride largely results from the loss of control of differential gene expression. This hypothesis is formulated based on published reports which indicated that mercuric chloride induced apoptosis, and transcriptional activation and/or suppression of several genes in the kidney, and based on our initial studies, that mercuric chloride down-regulated estrogen receptor alpha mRNA expression in the efferent ductules, and induced apoptosis in the testis of adult male rats. To test this hypothesis, we will test the effects of oral administration of mercuric chloride on differential expression of genes (repressed versus induced) using differential display PCR and relevant toxicity endpoints. Using micro-array, we will determine the effects of mercuric chloride on unique genes related to phase I and II metabolism, apoptosis, inflammation, DNA damage, cell transport, and oxidative stress in the kidney, efferent ductules, and the testis. Semi-quantitative PCR will be used to determine the effect on steroid hormone receptors (estrogen and androgen) in the efferent ductules and testis. The proposed experiments will identify pathways by which mercuric chloride causes toxicity, and identify molecular biomarkers for exposure to inorganic mercury. Such approach will be valuable in the identification of new drug targets for treatment of mercuric chloride.